US8088793B2 - Certain chemical entities, compositions, and methods - Google Patents

Certain chemical entities, compositions, and methods Download PDF

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US8088793B2
US8088793B2 US12/228,421 US22842108A US8088793B2 US 8088793 B2 US8088793 B2 US 8088793B2 US 22842108 A US22842108 A US 22842108A US 8088793 B2 US8088793 B2 US 8088793B2
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methyl
amino
isoquinolyl
carbamoyloxy
chloro
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US20090275537A1 (en
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Xiangping Qian
Chihyuan (Grace) Chuang
Pu-Ping Lu
Bing Yao
Qing (Kevin) Lu
Hong Jiang
Wenyue Wang
Bradley P. Morgan
David J. Morgans, Jr.
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Cytokinetics Inc
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Cytokinetics Inc
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Assigned to CYTOKINETICS, INC. reassignment CYTOKINETICS, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MORGAN, BRADLEY P, CHUANG, CHIHYUAN (GRACE), JIANG, HONG, LU, PU-PING, LU, QING (KEVIN), MORGANS, DAVID J., JR, WANG, WENYUE, YAO, BING, QIAN, XIANGPING
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    • C07D213/02—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members
    • C07D213/04—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D213/72—Nitrogen atoms
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    • C07D217/00—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems
    • C07D217/22—Heterocyclic compounds containing isoquinoline or hydrogenated isoquinoline ring systems with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to carbon atoms of the nitrogen-containing ring
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    • C07D261/00—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings
    • C07D261/02—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings
    • C07D261/06—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members
    • C07D261/10—Heterocyclic compounds containing 1,2-oxazole or hydrogenated 1,2-oxazole rings not condensed with other rings having two or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/60—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings condensed with carbocyclic rings or ring systems
    • C07D277/62—Benzothiazoles
    • C07D277/68—Benzothiazoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached in position 2
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    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
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    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/04—Ortho-condensed systems

Definitions

  • compositions and methods of treatment of diseases and conditions associated with smooth muscle myosin and/or non-muscle myosin are provided.
  • Myosin is present in all muscle and muscle cells. Of the ten distinct classes of myosin in human cells, myosin-II is thought to be the form responsible for contraction of skeletal, cardiac, and smooth muscle. Myosin-II is also the isoform present in non-muscle myosins, also known as cytoplasmic myosins. The non-muscle myosins are ubiquitously present in eukaryotic cells, where the smooth muscle myosins are generally present in smooth muscle cells.
  • Myosin-II is significantly different in amino acid composition and in overall structure from myosins in the other nine distinct classes.
  • Myosin-II consists of two globular head domains, called Subfragment-1 or S1, linked together by a long alpha-helical coiled-coiled tail.
  • S1 contains the ATPase and actin-binding properties of the molecule. S1 has been shown to be sufficient to move actin filaments in vitro, and is therefore likely to be the motor domain of the molecule.
  • myosin-II isoforms from various tissues differ in a number of biological properties, they share the same basic molecular structure as a dimer of two heavy chains (approximately 200 kDa) which are noncovalently associated with two pairs of light chains (approximately 20 and 17 kDa).
  • the two globular amino-terminal heads are tethered together by the carboxy-terminal alpha-helical coiled-coil that forms a tail.
  • the tails are believed to be involved in the assembly of myosin molecules into filaments, whereas the heads are thought to have an actin-activated Mg 2+ -ATPase activity.
  • Each myosin head can be divided by three protease-sensitive regions into peptides of approximately 25, 50, and 20 kDa. The more amino-terminal 25 kDa-50 kDa junction is close to the ATP binding region, whereas the actin-binding domain is near the 50 kDa-20 kDa junction.
  • S1 consists of a globular actin binding and nucleotide binding region known as the catalytic domain. This domain is attached at its carboxy-terminus to an alpha-helix that has two light chains of about 20 kDa each wrapped around it. This light-chain binding domain of 51 is known as the lever arm. Upon transitioning from the pre-stroke to the post-stroke state, the lever arm is believed to swing through an angle of about 90 degrees about a fulcrum point in the catalytic domain near the nucleotide-binding site. The “power stroke” is driven by the hydrolysis of ATP.
  • the other end of the myosin molecule is an alpha-helical coiled-coiled tail involved in self assembly of myosin molecules into bipolar thick filaments. These thick filaments interdigitate between thinner actin filaments, and the two filament systems slide past one another during contraction of the muscle. This filament sliding mechanism is thought to involve conformational changes in the myosin heads causing them to walk along the thin actin filaments at the expense of ATP hydrolysis. While non-muscle myosins act in a similar manner, they are understood to slide at a slower velocity than the smooth muscle myosins.
  • the complete cDNA of the human smooth muscle myosin has been described.
  • the sequence of human smooth muscle myosin is 52% identical to human cardiac myosin in the catalytic S1 region. See, for example, PCT publication No. WO 03/14323.
  • W 1 and W 2 are independently selected from CR 11 R 12 , NR 13 , and O; provided at least one of W 1 and W 2 is NR 13 ;
  • W 3 is selected from CR 1 R 2 , NR 14 , and O;
  • Z 1 is selected from heteroaryl and heterocycloalkyl
  • Z 2 is selected from aryl, heteroaryl, and heterocycloalkyl
  • R 8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
  • R 1 , R 2 , R 11 , and R 12 are independently selected from hydrogen, hydroxy, carboxy, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R 1 and R 2 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted
  • R 13 and R 14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;
  • R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, hydroxy, carboxy, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R 5 and R 6 taken together form an optionally substituted ring selected from optionally substituted
  • R 1 and one occurrence of R 5 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
  • R 14 and one occurrence of R 5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R 13 and R 1 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R 13 and one occurrence of R 5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R 7 and R 10 are independently selected from hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl, and optionally substituted alkynyl;
  • n 0, 1, 2, and 3;
  • n is selected from 0, 1, 2, 3, and 4;
  • p is selected from 0, 1, 2, and 3;
  • q is selected from 1, 2, 3, and 4.
  • composition comprising at least one chemical entity described herein, together with at least one pharmaceutically acceptable vehicle selected from carriers, adjuvants, and excipients.
  • the methods of treatment comprise administering a therapeutically effective amount of at least one chemical entity provided herein or a pharmaceutical composition comprising at least one chemical entity described herein, together with at least one pharmaceutically acceptable vehicle selected from carriers, adjuvants, and excipients.
  • Also provided are methods of treating or ameliorating a disease associated with airway wall remodeling in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity described herein.
  • a dash (“-”) that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, —CONH 2 is attached through the carbon atom.
  • optionally substituted alkyl encompasses both “alkyl” and “substituted alkyl” as defined below. It will be understood by those skilled in the art, with respect to any group containing one or more substituents, that such groups are not intended to introduce any substitution or substitution patterns that are sterically impractical, synthetically non-feasible and/or inherently unstable.
  • ATPase refers to an enzyme that is capable of hydrolyzing ATP.
  • ATPases include proteins comprising molecular motors such as myosins.
  • Alkyl encompasses straight chain and branched chain having the indicated number of carbon atoms, usually from 1 to 20 carbon atoms, for example 1 to 8 carbon atoms, such as 1 to 6 carbon atoms.
  • C 1 -C 6 alkyl encompasses both straight and branched chain alkyl of from 1 to 6 carbon atoms.
  • alkyl residue having a specific number of carbons is named, all branched and straight chain versions having that number of carbons are intended to be encompassed; thus, for example, “butyl” is meant to include n-butyl, sec-butyl, isobutyl and t-butyl; “propyl” includes n-propyl and isopropyl.
  • “Lower alkyl” refers to alkyl groups having one to six carbons. Examples of alkyl groups include methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, 3-methylpentyl, and the like.
  • Alkylene is a subset of alkyl, referring to the same residues as alkyl, but having two points of attachment. Alkylene groups will usually have from 2 to 20 carbon atoms, for example 2 to 8 carbon atoms, such as from 2 to 6 carbon atoms. For example, C 0 alkylene indicates a covalent bond and C 1 alkylene is a methylene group.
  • Alkenyl refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon double bond derived by the removal of one molecule of hydrogen from adjacent carbon atoms of the parent alkyl.
  • the group may be in either the cis or trans configuration about the double bond(s).
  • Typical alkenyl groups include, but are not limited to, ethenyl; propenyls such as prop-1-en-1-yl, prop-1-en-2-yl, prop-2-en-1-yl (allyl), prop-2-en-2-yl; butenyls such as but-1-en-1-yl, but-1-en-2-yl, 2-methyl-prop-1-en-1-yl, but-2-en-1-yl, but-2-en-1-yl, but-2-en-2-yl, buta-1,3-dien-1-yl, buta-1,3-dien-2-yl; and the like.
  • an alkenyl group has from 2 to 20 carbon atoms and in other embodiments, from 2 to 6 carbon atoms. “Lower alkenyl” refers to alkenyl groups having two to six carbons.
  • Alkynyl refers to an unsaturated branched or straight-chain alkyl group having at least one carbon-carbon triple bond derived by the removal of two molecules of hydrogen from adjacent carbon atoms of the parent alkyl.
  • Typical alkynyl groups include, but are not limited to, ethynyl; propynyls such as prop-1-yn-1-yl, prop-2-yn-1-yl; butynyls such as but-1-yn-1-yl, but-1-yn-3-yl, but-3-yn-1-yl; and the like.
  • an alkynyl group has from 2 to 20 carbon atoms and in other embodiments, from 3 to 6 carbon atoms.
  • “Lower alkynyl” refers to alkynyl groups having two to six carbons.
  • Cycloalkyl indicates a non-aromatic carbocyclic ring, usually having from 3 to 7 ring carbon atoms. The ring may be saturated or have one or more carbon-carbon double bonds. Examples of cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, and cyclohexenyl, as well as bridged and caged ring groups such as norbornane.
  • alkoxy is meant an alkyl group of the indicated number of carbon atoms attached through an oxygen bridge such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentyloxy, 2-pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, 2-hexyloxy, 3-hexyloxy, 3-methylpentyloxy, and the like.
  • Alkoxy groups will usually have from 1 to 7 carbon atoms attached through the oxygen bridge. “Lower alkoxy” refers to alkoxy groups having one to six carbons.
  • “Mono- and di-alkylcarboxamide” encompasses a group of the formula —(C ⁇ O)NR a R b where R a and R b are independently selected from hydrogen and alkyl groups of the indicated number of carbon atoms, provided that R a and R b are not both hydrogen.
  • Acyl refers to the groups H—C(O)—; (alkyl)-C(O)—; (cycloalkyl)-C(O)—; (aryl)-C(O)—; (heteroaryl)-C(O)—; and (heterocycloalkyl)-C(O)—, wherein the group is attached to the parent structure through the carbonyl functionality and wherein alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl are as described herein.
  • Acyl groups have the indicated number of carbon atoms, with the carbon of the keto group being included in the numbered carbon atoms.
  • a C 2 acyl group is an acetyl group having the formula CH 3 (C ⁇ O)—.
  • Forml refers to the group —C(O)H.
  • Carboxy and/or “carboxyl” refer to the group —C(O)OH.
  • alkoxycarbonyl is meant a group of the formula (alkoxy)(C ⁇ O)— attached through the carbonyl carbon wherein the alkoxy group has the indicated number of carbon atoms.
  • a C 1 -C 6 alkoxycarbonyl group is an alkoxy group having from 1 to 6 carbon atoms attached through its oxygen to a carbonyl linker.
  • azido is meant the group —N 3 .
  • amino is meant the group —NH 2 .
  • “Mono- and di-(alkyl)amino” encompasses secondary and tertiary alkyl amino groups, wherein the alkyl groups are as defined above and have the indicated number of carbon atoms. The point of attachment of the alkylamino group is on the nitrogen. Examples of mono- and di-alkylamino groups include ethylamino, dimethylamino, and methyl-propyl-amino.
  • aminocarbonyl refers to the group —CONR b R c , where
  • R b is selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl, optionally substituted alkoxy; and
  • R c is independently selected from hydrogen and optionally substituted C 1 -C 4 alkyl; or
  • R b and R c taken together with the nitrogen to which they are bound, form an optionally substituted 5- to 7-membered nitrogen-containing heterocycloalkyl which optionally includes 1 or 2 additional heteroatoms selected from O, N, and S in the heterocycloalkyl ring;
  • each substituted group is independently substituted with one or more substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl, —OC 1 -C 4 alkyl, —OC 1 -C 4 alkylphenyl, —C 1 -C 4 alkyl-OH, —OC 1 -C 4 haloalkyl, halo, —OH, —NH 2 , —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), —NH(C 1 -C 4 alkyl), —N(C 1 -
  • 6-membered carbocyclic aromatic rings for example, benzene
  • bicyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, naphthalene, indane, and tetralin; and
  • tricyclic ring systems wherein at least one ring is carbocyclic and aromatic, for example, fluorene.
  • aryl includes 6-membered carbocyclic aromatic rings fused to a 5- to 7-membered heterocycloalkyl ring containing 1 or more heteroatoms selected from N, O, and S.
  • bicyclic ring systems wherein only one of the rings is a carbocyclic aromatic ring, the point of attachment may be at the carbocyclic aromatic ring or the heterocycloalkyl ring.
  • Bivalent radicals formed from substituted benzene derivatives and having the free valences at ring atoms are named as substituted phenylene radicals.
  • Bivalent radicals derived from univalent polycyclic hydrocarbon radicals whose names end in “-yl” by removal of one hydrogen atom from the carbon atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g. a naphthyl group with two points of attachment is termed naphthylidene.
  • Aryl does not encompass or overlap in any way with heteroaryl, separately defined below. Hence, if one or more carbocyclic aromatic rings is fused with a heterocycloalkyl aromatic ring, the resulting ring system is heteroaryl, not aryl, as defined herein.
  • aryloxy refers to the group —O-aryl.
  • aralkyl refers to the group -alkyl-aryl.
  • Carbamimidoyl refers to the group —C( ⁇ NH)—NH 2 .
  • Substituted carbamimidoyl refers to the group —C( ⁇ NR e )—NR f R g where
  • R e is selected from hydrogen, cyano, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
  • R f and R g are independently selected from hydrogen optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl,
  • R e , R f , and R g is not hydrogen and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from
  • R a is selected from optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is selected from H, optionally substituted C1-C6 alkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R e is independently selected from hydrogen and optionally substituted C1-C4 alkyl
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl, —OC 1 -C 4 alkyl, —OC 1 -C 4 alkylphenyl, —C 1 -C 4 alkyl-OH, —OC 1 -C 4 haloalkyl, halo, —OH, —NH 2 , —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), —NH
  • halo includes fluoro, chloro, bromo, and iodo
  • halogen includes fluorine, chlorine, bromine, and iodine
  • Haloalkyl indicates alkyl as defined above having the specified number of carbon atoms, substituted with 1 or more halogen atoms, up to the maximum allowable number of halogen atoms.
  • Examples of haloalkyl include, but are not limited to, trifluoromethyl, difluoromethyl, 2-fluoroethyl, and penta-fluoroethyl.
  • Heteroaryl encompasses:
  • bicyclic heterocycloalkyl rings containing one or more, for example, from 1 to 4, or in certain embodiments, from 1 to 3, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring; and
  • tricyclic heterocycloalkyl rings containing one or more, for example, from 1 to 5, or in certain embodiments, from 1 to 4, heteroatoms selected from N, O, and S, with the remaining ring atoms being carbon and wherein at least one heteroatom is present in an aromatic ring.
  • heteroaryl includes a 5- to 7-membered heterocycloalkyl, aromatic ring fused to a 5- to 7-membered cycloalkyl or heterocycloalkyl ring.
  • bicyclic heteroaryl ring systems wherein only one of the rings contains one or more heteroatoms, the point of attachment may be at either ring.
  • the total number of S and O atoms in the heteroaryl group exceeds 1, those heteroatoms are not adjacent to one another.
  • the total number of S and O atoms in the heteroaryl group is not more than 2.
  • the total number of S and O atoms in the aromatic heterocycle is not more than 1.
  • heteroaryl groups include, but are not limited to, (as numbered from the linkage position assigned priority 1), 2-pyridyl, 3-pyridyl, 4-pyridyl, 2,3-pyrazinyl, 3,4-pyrazinyl, 2,4-pyrimidinyl, 3,5-pyrimidinyl, 2,3-pyrazolinyl, 2,4-imidazolinyl, isoxazolinyl, oxazolinyl, thiazolinyl, thiadiazolinyl, tetrazolyl, thienyl, benzothiophenyl, furanyl, benzofuranyl, benzoimidazolinyl, indolinyl, pyridazinyl, triazolyl, quinolinyl, pyrazolyl, and 5,6,7,8-tetrahydroisoquinolinyl.
  • heteroaryl groups include, but are not limited to, isoquinolinyl, isoxazol-3-yl, and isoxazol-5-yl.
  • Bivalent radicals derived from univalent heteroaryl radicals whose names end in “-yl” by removal of one hydrogen atom from the atom with the free valence are named by adding “-idene” to the name of the corresponding univalent radical, e.g. a pyridyl group with two points of attachment is a pyridylidene.
  • Heteroaryl does not encompass or overlap with aryl, cycloalkyl, or heterocycloalkyl, as defined herein
  • Substituted heteroaryl also includes ring systems substituted with one or more oxide (—O ⁇ ) substituents, such as pyridinyl N-oxides.
  • heterocycloalkyl is meant a single, non-aromatic ring, usually with 3 to 7 ring atoms, containing at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms.
  • the ring may be saturated or have one or more carbon-carbon double bonds.
  • Suitable heterocycloalkyl groups include, for example (as numbered from the linkage position assigned priority 1), 2-pyrrolidinyl, 2,4-imidazolidinyl, 2,3-pyrazolidinyl, 2-piperidyl, 3-piperidyl, 4-piperidyl, and 2,5-piperizinyl.
  • Morpholinyl groups are also contemplated, including 2-morpholinyl and 3-morpholinyl (numbered wherein the oxygen is assigned priority 1).
  • Substituted heterocycloalkyl also includes ring systems substituted with one or more oxo ( ⁇ O) or oxide (—O ⁇ ) substituents, such as piperidinyl N-oxide, morpholinyl-N-oxide, 1-oxo-1-thiomorpholinyl and 1,1-dioxo-1-thiomorpholinyl.
  • Heterocycloalkyl also includes bicyclic ring systems wherein one non-aromatic ring, usually with 3 to 7 ring atoms, contains at least 2 carbon atoms in addition to 1-3 heteroatoms independently selected from oxygen, sulfur, and nitrogen, as well as combinations comprising at least one of the foregoing heteroatoms; and the other ring, usually with 3 to 7 ring atoms, optionally contains 1-3 heteratoms independently selected from oxygen, sulfur, and nitrogen and is not aromatic.
  • modulation refers to a change in activity as a direct or indirect response to the presence of a chemical entity as described herein, relative to the activity of in the absence of the chemical entity.
  • the change may be an increase in activity or a decrease in activity, and may be due to the direct interaction of the compound with the a target or due to the interaction of the compound with one or more other factors that in turn affect the target's activity.
  • the presence of the chemical entity may, for example, increase or decrease the target activity by directly binding to the target, by causing (directly or indirectly) another factor to increase or decrease the target activity, or by (directly or indirectly) increasing or decreasing the amount of target present in the cell or organism.
  • sulfanyl includes the groups: —S-(optionally substituted (C 1 -C 6 )alkyl), —S-(optionally substituted aryl), —S-(optionally substituted heteroaryl), and —S-(optionally substituted heterocycloalkyl).
  • sulfanyl includes the group C 1 -C 6 alkylsulfanyl.
  • sulfinyl includes the groups: —S(O)-(optionally substituted (C 1 -C 6 )alkyl), —S(O)-optionally substituted aryl), —S(O)-optionally substituted heteroaryl), —S(O)-(optionally substituted heterocycloalkyl); and —S(O)-(optionally substituted amino).
  • sulfonyl includes the groups: —S(O 2 )-(optionally substituted (C 1 -C 6 )alkyl), —S(O 2 )-optionally substituted aryl), —S(O 2 )-optionally substituted heteroaryl), —S(O 2 )— (optionally substituted heterocycloalkyl), and —S(O 2 )-(optionally substituted amino).
  • substituted means that any one or more hydrogens on the designated atom or group is replaced with a selection from the indicated group, provided that the designated atom's normal valence is not exceeded.
  • a substituent is oxo (i.e. ⁇ O) then 2 hydrogens on the atom are replaced.
  • Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds or useful synthetic intermediates.
  • a stable compound or stable structure is meant to imply a compound that is sufficiently robust to survive isolation from a reaction mixture, and subsequent formulation as an agent having at least practical utility.
  • substituents are named into the core structure. For example, it is to be understood that when (cycloalkyl)alkyl is listed as a possible substituent, the point of attachment of this substituent to the core structure is in the alkyl portion.
  • substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from
  • —R a , —OR b optionally substituted amino (including —NR c COR b , —NR c CO 2 R a , —NR c CONR b R c , —NR b C(NR c )NR b R c , —NR b C(NCN)NR b R c , —NR b C(NH 2 )NC(O)NH 2 , —NR b C(NH 2 )N(CN), and —NR c SO 2 R a ), halo, cyano, azido, nitro, oxo (as a substitutent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as —COR b ), optionally substituted alkoxycarbonyl (such as —CO 2 R b ), aminocarbonyl (such as —CONR b R c ), —OCOR b , —OCO
  • R a is selected from optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently selected from hydrogen and optionally substituted C 1 -C 4 alkyl; or
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl, —OC 1 -C 4 alkyl, —OC 1 -C 4 alkylphenyl, —C 1 -C 4 alkyl-OH, —OC 1 -C 4 haloalkyl, halo, —OH, —NH 2 , —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), —NH
  • substituted acyl refers to the groups (substituted alkyl)-C(O)—; (substituted cycloalkyl)-C(O)—; (substituted aryl)-C(O)—; (substituted heteroaryl)-C(O)—; and (substituted heterocycloalkyl)-C(O)—, wherein the group is attached to the parent structure through the carbonyl functionality and wherein substituted alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl, refer respectively to alkyl, cycloalkyl, aryl, heteroaryl, and heterocycloalkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from
  • —R a , —OR b optionally substituted amino (including —NR c COR b , —NR c CO 2 R a , —NR c CONR b R c , —NR b C(NR c )NR b R c , —NR b C(NCN)NR b R c , and —NR c SO 2 R a ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as —COR b ), optionally substituted alkoxycarbonyl (such as —CO 2 R b ), aminocarbonyl (such as —CONR b R c ), —OCOR b , —OCO 2 R a , —OCONR b R c , —OP(O)(OR b )OR c , sulf
  • R a is selected from optionally substituted C 1 -C 6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently selected from hydrogen and optionally substituted C 1 -C 4 alkyl; or
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl, —OC 1 -C 4 alkyl, —OC 1 -C 4 alkylphenyl, —C 1 -C 4 alkyl-OH, —OC 1 -C 4 haloalkyl, halo, —OH, —NH 2 , —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), —NH
  • substituted alkoxy refers to alkoxy wherein the alkyl constituent is substituted (i.e. —O-(substituted alkyl)) wherein “substituted alkyl” refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from
  • —R a , —OR b optionally substituted amino (including —NR c COR b , —NR c CO 2 R a , —NR c CONR b R c , —NR b C(NR c )NR b R c , —NR b C(NCN)NR b R c , and —NR c SO 2 R a ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as —COR b ), optionally substituted alkoxycarbonyl (such as —CO 2 R b ), aminocarbonyl (such as —CONR b R c ), —OCOR b , —OCO 2 R a , —OCONR b R c , —OP(O)(OR b )OR c , sulf
  • R a is selected from optionally substituted C 1 -C 6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently selected from hydrogen and optionally substituted C 1 -C 4 alkyl; or
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl, —OC 1 -C 4 alkyl, —OC 1 -C 4 alkylphenyl, —C 1 -C 4 alkyl-OH, —OC 1 -C 4 haloalkyl, halo, —OH, —NH 2 , —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), —NH
  • a substituted alkoxy group is “polyalkoxy” or —O-(optionally substituted alkylene)-(optionally substituted alkoxy), and includes groups such as —OCH2CH2OCH3, and residues of glycol ethers such as polyethyleneglycol, and —O(CH2CH2O)xCH3, where x is an integer of 2-20, such as 2-10, and for example, 2-5.
  • Another substituted alkoxy group is hydroxyalkoxy or —OCH2(CH2)yOH, where y is an integer of 1-10, such as 1-4.
  • substituted alkoxycarbonyl refers to the group (substituted alkyl)-O—C(O)— wherein the group is attached to the parent structure through the carbonyl functionality and wherein substituted refers to alkyl wherein one or more (such as up to 5, for example, up to 3) hydrogen atoms are replaced by a substituent independently selected from
  • —R a , —OR b optionally substituted amino (including —NR c COR b , —NR c CO 2 R a , —NR c CONR b R c , —NR b C(NR c )NR b R c , —NR b C(NCN)NR b R c , and —NR c SO 2 R a ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as —COR b ), optionally substituted alkoxycarbonyl (such as —CO 2 R b ), aminocarbonyl (such as —CONR b R c ), —OCOR b , —OCO 2 R a , —OCONR b R c , —OP(O)(OR b )OR c , sulf
  • R a is selected from optionally substituted C 1 -C 6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently selected from hydrogen and optionally substituted C 1 -C 4 alkyl; or
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl, —OC 1 -C 4 alkyl, —OC 1 -C 4 alkylphenyl, —C 1 -C 4 alkyl-OH, —OC 1 -C 4 haloalkyl, halo, —OH, —NH 2 , —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), —NH
  • substituted amino refers to the group —NHR d or —NR d R e wherein R d is selected from hydroxy, formyl, optionally substituted alkoxy, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted acyl, optionally substituted carbamimidoyl, aminocarbonyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted alkoxycarbonyl, sulfinyl and sulfonyl, and wherein R e is selected from optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl, and wherein substituted alkyl, cycloalkyl, aryl, heterocycloalkyl, and heteroaryl refer respectively to alkyl, cycloalkyl, aryl, heterocycloalkyl
  • —R a , —OR b optionally substituted amino (including —NR c COR b , —NR c CO 2 R a , —NR c CONR b R c , —NR b C(NR c )NR b R c , —NR b C(NCN)NR b R c , and —NR c SO 2 R a ), halo, cyano, nitro, oxo (as a substitutent for cycloalkyl or heterocycloalkyl), optionally substituted acyl (such as —COR b ), optionally substituted alkoxycarbonyl (such as —CO 2 R b ), aminocarbonyl (such as —CONR b R c ), —OCOR b , —OCO 2 R a , —OCONR b R c , —OP(O)(OR b )OR c , sulf
  • R a is selected from optionally substituted C 1 -C 6 alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R b is selected from H, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl;
  • R c is independently selected from hydrogen and optionally substituted C 1 -C 4 alkyl; or
  • R b and R c and the nitrogen to which they are attached, form an optionally substituted heterocycloalkyl group
  • each optionally substituted group is unsubstituted or independently substituted with one or more, such as one, two, or three, substituents independently selected from C 1 -C 4 alkyl, aryl, heteroaryl, aryl-C 1 -C 4 alkyl-, heteroaryl-C 1 -C 4 alkyl-, C 1 -C 4 haloalkyl, —OC 1 -C 4 alkyl, —OC 1 -C 4 alkylphenyl, —C 1 -C 4 alkyl-OH, —OC 1 -C 4 haloalkyl, halo, —OH, —NH 2 , —C 1 -C 4 alkyl-NH 2 , —N(C 1 -C 4 alkyl)(C 1 -C 4 alkyl), —NH(C 1 -C 4 alkyl), —N(C 1 -C 4 alkyl)(C 1 -C 4 alkylphenyl), —NH
  • substituted amino also refers to N-oxides of the groups —NHR d , and NR d R d each as described above.
  • N-oxides can be prepared by treatment of the corresponding amino group with, for example, hydrogen peroxide or m-chloroperoxybenzoic acid. The person skilled in the art is familiar with reaction conditions for carrying out the N-oxidation.
  • phosphato refers to —OP(O)(OR b )OR c where R b is selected from hydrogen, optionally substituted C 1 -C 6 alkyl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aryl, and optionally substituted heteroaryl; and R c is independently selected from hydrogen and optionally substituted C 1 -C 4 alkyl. In some embodiments, R b and R c are hydrogen.
  • Compounds of Formula I include, but are not limited to, optical isomers of compounds of Formula I, racemates, and other mixtures thereof.
  • the single enantiomers or diastereomers, i.e. optically active forms can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral high-pressure liquid chromatography (HPLC) column.
  • compounds of Formula I include Z- and E-forms (or cis- and trans-forms) of compounds with carbon-carbon double bonds. Where compounds of Formula I exists in various tautomeric forms, chemical entities described herein include all tautomeric forms of the compound.
  • Chemical entities described herein include, but are not limited to compounds of Formula I and all pharmaceutically acceptable forms thereof.
  • Pharmaceutically acceptable forms of the chemical entities recited herein include pharmaceutically acceptable salts, solvates, crystal forms (including polymorphs and clathrates), chelates, non-covalent complexes, prodrugs, and mixtures thereof.
  • the chemical entities described herein are in the form of pharmaceutically acceptable salts.
  • the terms “chemical entity” and “chemical entities” also encompass pharmaceutically acceptable salts, solvates, chelates, non-covalent complexes, prodrugs, and mixtures.
  • “Pharmaceutically acceptable salts” include, but are not limited to salts with inorganic acids, such as hydrochloride, phosphate, diphosphate, hydrobromide, sulfate, sulfinate, nitrate, and like salts; as well as salts with an organic acid, such as malate, maleate, fumarate, tartrate, succinate, citrate, lactate, methanesulfonate, p-toluenesulfonate, 2-hydroxyethylsulfonate, benzoate, salicylate, stearate, and alkanoate such as acetate, HOOC—(CH 2 ) n —COOH where n is 0-4, and like salts.
  • pharmaceutically acceptable cations include, but are not limited to sodium, potassium, calcium, aluminum, lithium, and ammonium.
  • the free base can be obtained by basifying a solution of the acid salt.
  • an addition salt particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
  • Those skilled in the art will recognize various synthetic methodologies that may be used to prepare non-toxic pharmaceutically acceptable addition salts.
  • prodrugs also fall within the scope of chemical entities, for example ester or amide derivatives of the compounds of Formula I.
  • the term “prodrugs” includes any chemical entities that become compounds of Formula I when administered to a patient, e.g. upon metabolic processing of the prodrug.
  • Examples of prodrugs include, but are not limited to, acetate, formate, phosphate, and benzoate and like derivatives of functional groups (such as alcohol or amine groups) in the compounds of Formula I.
  • solvate refers to the chemical entity formed by the interaction of a solvent and a compound. Suitable solvates are pharmaceutically acceptable solvates, such as hydrates, including monohydrates and hemi-hydrates.
  • chelate refers to the chemical entity formed by the coordination of a compound to a metal ion at two (or more) points.
  • non-covalent complex refers to the chemical entity formed by the interaction of a compound and another molecule wherein a covalent bond is not formed between the compound and the molecule.
  • complexation can occur through van der Waals interactions, hydrogen bonding, and electrostatic interactions (also called ionic bonding).
  • an “active agent” is used to indicate a chemical entity which has biological activity.
  • an “active agent” is a compound having pharmaceutical utility.
  • an active agent may be an anti-cancer therapeutic.
  • significant is meant any detectable change that is statistically significant in a standard parametric test of statistical significance such as Student's T-test, where p ⁇ 0.05.
  • terapéuticaally effective amount of a chemical entity described herein means an amount effective, when administered to a human or non-human patient, to provide a therapeutic benefit such as amelioration of symptoms, slowing of disease progression, or prevention of disease.
  • Treatment or “treating” means any treatment of a disease in a patient, including:
  • Patient refers to an animal, such as a mammal, that has been or will be the object of treatment, observation or experiment. The methods described herein can be useful in both human therapy and veterinary applications.
  • the patient is a mammal; in some embodiments the patient is human; and in some embodiments the patient is selected from cats and dogs.
  • W 1 and W 2 are independently selected from CR 11 R 12 , NR 13 , and O; provided at least one of W 1 and W 2 is NR 13 ;
  • W 3 is selected from CR 1 R 2 , NR 14 , and O;
  • Z 1 is selected from heteroaryl and heterocycloalkyl
  • Z 2 is selected from aryl, heteroaryl, and heterocycloalkyl
  • R 8 is selected from hydrogen, optionally substituted alkyl, optionally substituted cycloalkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, and optionally substituted heterocycloalkyl;
  • R 1 , R 2 , R 11 , and R 12 are independently selected from hydrogen, hydroxy, carboxy, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R 1 and R 2 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted
  • R 13 and R 14 are independently selected from hydrogen, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, and optionally substituted heterocycloalkyl;
  • R 3 , R 4 , R 5 , and R 6 are independently selected from hydrogen, hydroxy, carboxy, sulfonyl, sulfinyl, sulfanyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted alkynyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted aminocarbonyloxy, optionally substituted acyloxy, optionally substituted alkoxycarbonyloxy, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted amino, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted cycloalkyl, optionally substituted heterocycloalkyl, optionally substituted aminocarbonyl, and optionally substituted aminosulfonyl; or R 5 and R 6 taken together form an optionally substituted ring selected from optionally substituted
  • R 1 and one occurrence of R 5 may optionally be joined together with any intervening atoms to form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl;
  • R 14 and one occurrence of R 5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R 13 and R 1 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R 13 and one occurrence of R 5 may optionally be joined together with any intervening atoms to form an optionally substituted heterocycloalkyl ring;
  • R 7 and R 10 are independently selected from hydrogen, cyano, halo, hydroxy, azido, nitro, carboxy, sulfinyl, sulfanyl, optionally substituted alkoxy, optionally substituted aryloxy, optionally substituted heteroaryloxy, optionally substituted heterocycloalkyloxy, optionally substituted alkoxycarbonyl, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryloxy, optionally substituted aryl, optionally substituted heteroaryl, optionally substituted heterocycloalkyl, optionally substituted amino, optionally substituted acyl, optionally substituted alkoxycarbonyl, optionally substituted aminocarbonyl, optionally substituted aminosulfonyl, optionally substituted carbaminodoyl, and optionally substituted alkynyl;
  • n 0, 1, 2, and 3;
  • n is selected from 0, 1, 2, 3, and 4;
  • p is selected from 0, 1, 2, and 3;
  • q is selected from 1, 2, 3, and 4.
  • Z 1 is selected from heteroaryl and heterocycloalkyl.
  • Z 1 is selected from quinolinyl, isoquinolinyl, pyridino[4,3-d]pyridinyl, benzothiazolyl, thiadiazolyl, pyridino[3,4-d]pyridinyl, pyridinyl, pyridino[3,2-d]pyridinyl, 8-hydropyrrolo[1,2-e]pyrimidinyl, isoxazolyl, 8-hydropyrazolo[1,5-a]pyridinyl, pyridino[2,3-d]pyridinyl, benzo[d]isozaolyl, pyrazinyl, thiazolyl, 4-oxo-3-hydroquinazolinyl, 4-hydroimidazo[1,2-a]pyridinyl, 1,3-thiazolo[5,4-b]pyridinyl,
  • Z 1 is selected from isoquinolin-3-yl, benzo[d]thiazol-2-yl, benzo[d]oxazol-2-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, quinolin-2-yl, quinolin-3-yl, thiazol-5-yl, thien-2-yl, and pyrrolo[1,2-c]pyrimidin-3-yl.
  • Z 2 is selected from aryl, heteroaryl, and heterocycloalkyl. In some embodiments, Z 2 is selected from phenyl, naphthyl, and indanyl. In some embodiments, Z 2 is phenyl.
  • W 1 is CR 11 R 12 .
  • R 11 and R 12 are each independently selected from hydrogen and optionally substituted lower alkyl.
  • R 11 and R 12 are each independently selected from hydrogen and lower alkyl.
  • R 11 and R 12 are both hydrogen.
  • W 1 is NR 13 .
  • R 13 is selected from hydrogen and optionally substituted lower alkyl.
  • R 13 is selected from hydrogen and lower alkyl.
  • R 13 is hydrogen
  • W 1 is O.
  • W 2 is CR 11 R 12 .
  • R 11 and R 12 are each independently selected from hydrogen and optionally substituted lower alkyl.
  • R 11 and R 12 are each independently selected from hydrogen and lower alkyl.
  • R 11 and R 12 are both hydrogen.
  • W 2 is NR 13 .
  • R 13 is selected from hydrogen and optionally substituted lower alkyl.
  • R 13 is selected from hydrogen and lower alkyl.
  • R 13 is hydrogen
  • W 2 is O.
  • W 1 is O and W 2 is NR 13 .
  • R 13 is hydrogen.
  • W 3 is CR 1 R 2 .
  • R 1 and R 2 are independently selected from hydrogen and optionally substituted alkyl.
  • R 1 and R 2 are independently selected from hydrogen and optionally substituted lower alkyl.
  • R 1 and R 2 are independently selected from hydrogen and lower alkyl.
  • R 1 and R 2 are independently selected from hydrogen and methyl.
  • R 1 and R 2 together with the carbon to which they are attached, form a group selected from optionally substituted cycloalkyl and optionally substituted heterocycloalkyl.
  • R 1 and R 2 together with the carbon to which they are attached, form a group selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, piperidinyl, and tetrahydropyranyl, any of which is optionally substituted.
  • R 1 and R 2 together with the carbon to which they are attached, form a group selected from piperidine and tetrahydropyran, either of which is optionally substituted with 2-aminoacetyl or 2-(tert-butoxycarbonylamino)acetyl.
  • R 1 and R 2 together with the carbon to which they are attached, form a group selected from tetrahydropyran, 1-(2-(tert-butoxycarbonylamino)acetyl)piperidin-4-yl, and 1-(2-aminoacetyl)piperidin-4-yl.
  • W 3 is NR 14 .
  • R 14 is selected from hydrogen and optionally substituted lower alkyl.
  • R 14 is selected from hydrogen, lower alkyl, and lower alkyl substituted with one or two groups selected from hydroxy, halo, optionally substituted amino, and optionally substituted alkoxy.
  • R 14 is selected from hydrogen, lower alkyl, and lower alkyl substituted with one or two groups selected from hydroxy, optionally substituted amino, and optionally substituted alkoxy.
  • R 14 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl, wherein methyl, ethyl, propyl, and isopropyl are optionally substituted with one or two groups selected from hydroxy, optionally substituted amino, and optionally substituted alkoxy.
  • R 14 is selected from hydrogen, methyl, ethyl, propyl, and isopropyl, wherein methyl, ethyl, propyl, and isopropyl are optionally substituted with one or two hydroxy groups.
  • R 14 is selected from methyl, ethyl, hydroxymethyl, 2-hydroxyethyl, 2,2-difluoroethyl, and isopropyl.
  • R 14 is selected from methyl, ethyl, hydroxymethyl, 2-hydroxyethyl, and isopropyl.
  • R 14 is selected from methyl and ethyl. In some embodiments, R 14 is methyl.
  • R 8 is selected from hydrogen and optionally substituted lower alkyl.
  • R 8 is selected from hydrogen and lower alkyl.
  • R 8 is selected from hydrogen and methyl.
  • R 8 is hydrogen
  • q is 3.
  • q is 2.
  • q is 1.
  • each R 5 is independently selected from hydrogen, optionally substituted lower alkyl, and optionally substituted alkenyl.
  • each R 5 is independently selected from hydrogen and optionally substituted lower alkyl.
  • each R 5 is independently selected from hydrogen, lower alkyl, and lower alkyl substituted with one, two, or three groups selected from optionally substituted heterocycloalkyl, optionally substituted heteroaryl, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, hydroxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl, halo, and azido.
  • each R 5 is independently selected from hydrogen, lower alkyl, and lower alkyl substituted with one, two, or three groups selected from optionally substituted heterocycloalkyl, optionally substituted alkoxy, optionally substituted alkoxycarbonyl, hydroxy, optionally substituted amino, optionally substituted aminocarbonyl, acyl, and azido.
  • each R 5 is independently selected from hydrogen, lower alkyl, and lower alkyl substituted with one, two, or three groups selected from 4-(lower alkyl)piperazin-1-yl, oxopiperazin-1-yl, morpholino, benzyloxy, benzyloxycarbonyl, methoxycarbonyl, hydroxy, amino, dimethylamino, methoxy(methyl)carbamoyl, acetamido, acetyl, and azido.
  • each R 5 is independently selected from hydrogen, methyl, ethyl, isopropyl, isobutyl, n-propyl, n-butyl, n-pentyl, isopentyl, and 4-methylpentyl, wherein each of methyl, ethyl, isopropyl, isobutyl, n-propyl, n-butyl, n-pentyl, isopentyl, and 4-methylpentyl is optionally substituted with one, two, or three groups selected from 4-methylpiperazin-1-yl, 3-oxopiperazin-1-yl, morpholino, benzyloxy, benzyloxycarbonyl, methoxycarbonyl, hydroxy, amino, dimethylamino, methoxy(methyl)carbamoyl, acetamido, acetyl, and azido.
  • each R 5 is independently selected from hydrogen, ethyl, 2-(benzyloxy)-2-oxoethyl, benzyloxymethyl, isobutyl, isopropyl, methyl, 2-hydroxyethyl, 2-methoxy-2-oxoethyl, 3-(benzyloxy)-3-oxopropyl, 3-hydroxypropyl, 3-methoxy-3-oxopropyl, 4-aminobutyl, 4-azidobutyl, 4-hydroxybutyl, 4-methoxy-4-oxobutyl, hydroxymethyl, 2-hydroxy-2-methylpropyl, 4-hydroxy-4-methylpentyl, 3-aminopropyl, (4-methylpiperazin-1-yl)methyl, 2-(3-oxopiperazin-1-yl)ethyl, morpholinoethyl, morpholinomethyl, (3-oxopiperazin-1-yl)methyl, (4-methylpiperaz
  • each R 6 is independently selected from hydrogen and optionally substituted lower alkyl.
  • each R 6 is independently selected from hydrogen and lower alkyl.
  • R 6 is hydrogen
  • —(CR 5 R 6 ) q — is —CH 2 CH(R 5 )— wherein R 5 is selected from hydrogen, lower alkyl, and lower alkyl substituted with one, two, or three groups selected from 4-(lower alkyl)piperazin-1-yl, oxopiperazin-1-yl, morpholino, benzyloxy, benzyloxycarbonyl, methoxycarbonyl, hydroxy, amino, dimethylamino, methoxy(methyl)carbamoyl, acetamido, acetyl, azido, phosphato (such as —OP(O)(OH) 2 ), and halo.
  • R 5 is selected from hydrogen, lower alkyl, and lower alkyl substituted with one, two, or three groups selected from 4-(lower alkyl)piperazin-1-yl, oxopiperazin-1-yl, morpholino, benzyloxy, benzyloxycarbonyl,
  • —(CR 5 R 6 ) q — is —CH 2 CH(R 5 )— wherein R 5 is lower alkyl substituted with one, two, or three groups selected from hydroxy and phosphato (such as —OP(O)(OH) 2 ).
  • —(CR 5 R 6 ) q — is —CH 2 CH(R 5 )— wherein R 5 is lower alkyl substituted with —OP(O)(OH) 2 and optionally further substituted with one or two hydroxy groups.
  • —(CR 5 R 6 ) q — is —CH 2 CH(R 5 )— wherein R 5 is lower alkyl substituted with optionally substituted heteroaryl.
  • R 5 is lower alkyl substituted with imidazol-4-yl, imidazol-2-yl, pyridin-2-yl, 1,2,4-oxadiazol-5-yl, isoxazol-5-yl, imidazo[1,5-a]piperazin-3-yl, or 4-hydroimidazo[1,5-a]pyrazin-3-yl, each of which is optionally substituted.
  • R 5 is lower alkyl substituted with imidazol-4-yl, imidazol-2-yl, pyridin-2-yl, 1,2,4-oxadiazol-5-yl, isoxazol-5-yl, imidazo[1,5-a]piperazin-3-yl, or 4-hydroimidazo[1,5-a]pyrazin-3-yl, each of which is optionally substituted with a lower alkyl group.
  • —(CR 5 R 6 ) q — is —CH 2 CH(R 5 )— wherein R 5 is lower alkyl substituted with optionally substitute aminocarbonyl.
  • R 5 is lower alkyl substituted with —C(O)NR 11 R 12 wherein R 11 and R 12 , together with the nitrogen to which they are bound, form an optionally substituted 5- to 7-membered heterocycloalkyl ring or optionally substituted 8- to 12-membered bicyclic heterocycloalkyl ring, each of which optionally includes an additional heteroatom chosen from oxygen, sulfur, and nitrogen.
  • R 5 is lower alkyl substituted with —C(O)NR 11 R 12 wherein R 11 and R 12 , together with the nitrogen to which they are bound, form a ring chosen from 4-piperazinyl, 1,4-diazaperhydroepinyl, and 4,5,6,7-tetrahydroimidazo[5,4-c]pyridin-5-yl, each of which is optionally substituted.
  • R 5 is lower alkyl substituted with —C(O)NR 11 R 12 wherein R 11 and R 12 , together with the nitrogen to which they are bound, form a 4-piperazinyl ring which is optionally substituted.
  • R 5 is lower alkyl substituted with —C(O)NR 11 R 12 wherein R 11 and R 12 , together with the nitrogen to which they are bound, form a 4-piperazinyl ring which is optionally substituted with one or two groups chosen from lower alkyl, hydroxy substituted lower alkyl, and halo substituted lower alkyl.
  • W 2 is NH
  • W 1 is O
  • W 3 is CR 1 R 2 .
  • W 2 is NH
  • W 1 is CH 2
  • W 3 is NR 14 .
  • W 2 is NH
  • W 1 is O
  • W 3 is NR 14 .
  • m is 0.
  • m is selected from 1 and 2
  • each R 7 is selected from halo and optionally substituted alkyl.
  • R 7 is selected from halo and optionally substituted lower alkyl.
  • R 7 is selected from halo and lower alkyl.
  • each R 7 is selected from chloro, fluoro, and methyl.
  • —(R 7 ) m together with Z 2 to which it is attached, forms a group selected from 2-chlorophenyl, 2-methylphenyl, 2-chloro-4-fluorophenyl, 2-chloro-3-fluorophenyl, 2,3-dichlorophenyl, 2,3-difluorophenyl, 2,4-dichlorophenyl, 2,4-difluorophenyl, and 3-chloro-2-fluorophenyl.
  • n is selected from 1 and 2.
  • n 1
  • each R 3 and R 4 is independently selected from hydrogen and optionally substituted lower alkyl.
  • each R 3 and R 4 is independently selected from hydrogen, methyl, ethyl, isopropyl, and hydroxymethyl.
  • R 3 and R 4 is hydrogen.
  • Z 1 is heteroaryl
  • p is selected from 0, 1, and 2
  • R 10 is selected from halo, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted heterocycloalkyl, and optionally substituted aryl.
  • Z 1 is heteroaryl
  • p is selected from 0, 1, and 2
  • R 10 is selected from halo, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted aryl.
  • Z 1 is isoquinolinyl, p is 1, and R 10 is halo. In some embodiments, Z 1 is 6-fluoroisoquinolin-3-yl.
  • Z 1 is pyridin-2-yl, p is 1, and R 10 is chosen from halo and optionally substituted lower alkyl. In some embodiments, Z 1 is pyridin-2-yl, p is 1, and R 10 is chosen from halo and trifluoromethyl.
  • Z 1 is isoxazol-3-yl, p is 1, and R 10 is chosen from optionally substituted phenyl. In some embodiments, Z 1 is isoxazol-3-yl, p is 1, and R 10 is chosen from phenyl and halophenyl.
  • Z 1 is isoxazol-5-yl, p is 1, and R 10 is chosen from optionally substituted phenyl. In some embodiments, Z 1 is isoxazol-5-yl, p is 1, and R 10 is chosen from phenyl and halophenyl.
  • p is 0 and Z 1 is selected from 2,7-naphthyridinyl, isoquinolinyl, benzo[d]thiazolyl, benzo[d]oxazolyl, 1,3,4-thiadiazolyl, pyridinyl, quinolinyl, thiazolyl, thienyl, and pyrrolo[1,2-c]pyrimidinyl.
  • p is 0 and Z 1 is selected from isoquinolinyl, benzo[d]thiazolyl, benzo[d]oxazolyl, 1,3,4-thiadiazolyl, pyridinyl, quinolinyl, thiazolyl, thienyl, and pyrrolo[1,2-c]pyrimidinyl.
  • p is 0 and Z 1 is isoquinolin-3-yl. In some embodiments, p is 0 and Z 1 is benzo[d]thiazolyl.
  • p is 0 and Z 1 is 2,7-naphthyridin-3-yl.
  • Z 1 is selected from isoquinolin-3-yl, isoxazol-5-yl, isoxazol-3-yl, benzo[d]thiazol-2-yl, benzo[d]oxazol-2-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, quinolin-2-yl, quinolin-3-yl, thiazol-5-yl, thien-2-yl, and pyrrolo[1,2-c]pyrimidin-3-yl.
  • p is selected from 1 and 2
  • each R 10 is independently selected from halo, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted aryl.
  • Z 1 is selected from isoquinolin-3-yl, benzo[d]thiazol-2-yl, benzo[d]oxazol-2-yl, 1,3,4-thiadiazol-2-yl, pyridin-2-yl, quinolin-2-yl, quinolin-3-yl, thiazol-5-yl, thien-2-yl, and pyrrolo[1,2-c]pyrimidin-3-yl.
  • p is selected from 1 and 2
  • each R 10 is independently selected from halo, optionally substituted alkyl, optionally substituted alkenyl, and optionally substituted aryl.
  • R 10 is independently selected from halo, optionally substituted lower alkyl, optionally substituted lower alkenyl, and optionally substituted phenyl.
  • R 10 is independently selected from chloro, fluoro, bromo, trifluoromethyl, methyl, ethyl, vinyl, and phenyl.
  • Z 1 is isoquinolin-3-yl, p is selected from 1 and 2, and each R 10 is independently selected from halo. In some embodiments, Z 1 is isoquinolin-3-yl, p is selected from 1 and 2, and each R 10 is fluoro. In some embodiments, Z 1 is isoquinolin-3-yl, p is 1, and R 10 is fluoro.
  • Z 1 is isoxazol-5-yl, p is 1, and R 10 is selected from optionally substituted phenyl. In some embodiments, Z 1 is isoxazol-5-yl, p is 1, and R 10 is selected from phenyl optionally substituted with one or two halo groups.
  • Z 1 is isoxazol-3-yl, p is 1, and R 10 is selected from optionally substituted phenyl. In some embodiments, Z 1 is isoxazol-3-yl, p is 1, and R 10 is selected from phenyl optionally substituted with one or two halo groups.
  • Z 1 is 1,3,4-thiadiazol-2-yl, p is 1, and R 10 is selected from optionally substituted phenyl. In some embodiments, Z 1 is isoxazol-3-yl, p is 1, and R 10 is selected from phenyl optionally substituted with one or two halo groups.
  • —(R 10 ) p together with Z 1 , forms a group selected from 3-phenylisoxazol-5-yl, 5-phenylisoxazol-3-yl, 6-methylbenzo[d]thiazol-2-yl, 5-ethylpyridin-2-yl, 4-methylbenzo[d]thiazol-2-yl, 5,6-dichlorobenzo[d]thiazol-2-yl, 5,6-difluorobenzo[d]thiazol-2-yl, 5,6-dimethylbenzo[d]thiazol-2-yl, 5-bromopyridin-2-yl, 5-phenyl-1,3,4-thiadiazol-2-yl, 5-vinylpyridin-2-yl, 6-fluoroisoquinolin-3-yl, 5-fluoroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl, 6-(trifluoromethyl)benzo[d]thiazol
  • —(R 10 ) p together with Z 1 , forms a group selected from 6-methylbenzo[d]thiazol-2-yl, 5-ethylpyridin-2-yl, 4-methylbenzo[d]thiazol-2-yl, 5,6-dichlorobenzo[d]thiazol-2-yl, 5,6-difluorobenzo[d]thiazol-2-yl, 5,6-dimethylbenzo[d]thiazol-2-yl, 5-bromopyridin-2-yl, 5-phenyl-1,3,4-thiadiazol-2-yl, 5-vinylpyridin-2-yl, 6-fluoroisoquinolin-3-yl, 5-fluoroisoquinolin-3-yl, 7-fluoroisoquinolin-3-yl, 6-(trifluoromethyl)benzo[d]thiazol-2-yl, 5-phenylpyridin-2-yl, 4-methyl-2-phenylthiazol-5
  • the chemical entites described herein can be synthesized utilizing techniques well known in the art from commercially available starting materials and reagents.
  • the chemical entites described herein can be prepared as illustrated below with reference to the examples and reaction schemes.
  • reaction times and conditions are intended to be approximate, e.g. taking place at about atmospheric pressure within a temperature range of about ⁇ 10° C. to about 110° C. over a period of about 1 to about 24 hours; reactions left to run overnight average a period of about 16 hours.
  • one cc (or mL) of solvent constitutes a volume equivalent.
  • solvent each mean a solvent inert under the conditions of the reaction being described in conjunction therewith [including, for example, benzene, toluene, acetonitrile, tetrahydrofuran (“THF”), dimethylformamide (“DMF”), chloroform, methylene chloride (or dichloromethane), diethyl ether, methanol, N-methylpyrrolidone (“NMP”), pyridine and the like].
  • solvents used in the reactions described herein are inert organic solvents.
  • one cc (or mL) of solvent constitutes a volume equivalent.
  • Isolation and purification of the compounds and intermediates described herein can be effected, if desired, by any suitable separation or purification procedure such as, for example, filtration, extraction, crystallization, column chromatography, thin-layer chromatography or thick-layer chromatography, or a combination of these procedures.
  • suitable separation and isolation procedures can be had by reference to the examples hereinbelow. However, other equivalent separation or isolation procedures can also be used.
  • the (R) and (S) isomers may be resolved by methods known to those skilled in the art, for example by formation of diastereoisomeric salts or complexes which may be separated, for example, by crystallization; via formation of diastereoisomeric derivatives which may be separated, for example, by crystallization, gas-liquid or liquid chromatography; selective reaction of one enantiomer with an enantiomer-specific reagent, for example enzymatic oxidation or reduction, followed by separation of the modified and unmodified enantiomers; or gas-liquid or liquid chromatography in a chiral environment, for example on a chiral support, such as silica with a bound chiral ligand or in the presence of a chiral solvent.
  • a further step may be required to liberate the desired enantiomeric form.
  • a specific enantiomer may be synthesized by asymmetric synthesis using optically active reagents, substrates, catalysts and/or solvents, or by converting one enantiomer to the other by asymmetric transformation.
  • the chemical entities described herein may be useful in a variety of applications involving smooth muscle cells and/or non-muscle cells.
  • the chemical entities may be used to inhibit smooth muscle myosin.
  • the chemical entities may be useful to bind to, and/or inhibit the activity of, smooth muscle myosin.
  • the smooth muscle myosin is human, although the chemical entities may be used to bind to or inhibit the activity of smooth muscle myosin from other organisms, such as other mammals.
  • the chemical entities may be used to inhibit non-muscle myosin.
  • the chemical entities may be useful to bind to, and/or inhibit the activity of, non-muscle myosin.
  • the non-muscle myosin is human, although the chemical entities may be used to bind to or inhibit the activity of non-muscle myosin from other organisms, such as other mammals.
  • the chemical entities described herein may be used to treat disease states associated with smooth muscle and/or non-muscle myosin.
  • disease states which can be treated by the chemical entities described herein include, but are not limited to, hypertension, asthma, incontinence, chronic obstructive pulmonary disorder, pre-term labor, and the like. It is appreciated that in some cases the cells may not be in an abnormal state and still require treatment.
  • disease states which may be treated by the chemical entities described herein include, but are not limited to, systemic hypertension, chronic heart failure, migraine and outpatient treatment of angina, pulmonary hypertension, perioperative hypertension, hypertensive emergency, cerebral vasospasm after cerebrovascular hemorrhage, in-hospital treatment of angina (including atypical angina) and/or acute heart failure.
  • Additional disease states which may be treated include, but are not limited to, Also bronchospasm, asthma, cardiovascular, cerebrovascular and peripheral vascular diseases, vasospasm after cerebrovascular hemorrhage, erectile dysfunction, gastrointestinal motility dysfunction (e.g., irritable bowel syndrome), overactive bladder/stress urinary incontinence, and preterm labor.
  • the chemical entities described herein are applied to cells or administered to individuals afflicted or subject to impending affliction with any one of these disorders or states.
  • the chemical entities described herein may be useful for the treatment of diseases or symptoms related to abnormal increased muscle tone or excessive contraction, or spasm of vascular smooth muscle in systemic, coronary, pulmonary circulation, and micro-circulatory smooth muscle as well, such as systemic hypertension, malignant hypertension, hypertension crisis, symptomatic hypertension, pulmonary hypertension, pulmonary infarction, angina pectoris, cardiac infarction, micro-circulation malfunction under shock condition, and infarction occurred in other location or organs of the human or animal body.
  • diseases or symptoms that can be treated with the chemical entities described herein include:
  • spasm of gastro-intestine smooth muscle including sphincters, such as gastric spasm, pylorospasm, and spasms of biliary tract, pancreatic tract, urinary tract, caused by inflammation, stimulation of stones or parasites;
  • sphincters such as gastric spasm, pylorospasm, and spasms of biliary tract, pancreatic tract, urinary tract, caused by inflammation, stimulation of stones or parasites
  • the chemical entities described herein can be used for control, management and manipulation of labor during pregnancy.
  • the method is particularly useful for inhibition of spontaneous preterm labor which would, if untreated, result in premature delivery or abortion and for inhibition of surgically induced labor during transuterine fetal surgery.
  • the method is also useful for inducing the labor in overterm pregnancies where the labor does not occur on term and when it is necessary to induce labor in order to assure the normal delivery.
  • airway wall remodeling is a condition associated with diseases or conditions characterized by airway wall thickening and air obstruction, which may, for example, occur in the small airways of patients with certain respiratory disease conditions, such as chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • Such disease states which can be treated by the chemical entities, compositions and methods provided herein also include, but are not limited to glaucoma and other ocular indications. More specifically, chemical entities described herein may be useful for the treatment of diseases or symptoms related to glaucoma, including increased intraocular pressure, reduced flow of intraocular aqueous humor, and optical nerve damage. Other diseases or symptoms that can be treated with the chemical entities, compositions, and methods described herein including intraocular hypertenstion.
  • ATP hydrolysis is employed by myosin to produce force.
  • An increase in ATP hydrolysis would correspond to an increase in the force or velocity of muscle contraction.
  • myosin ATPase activity is stimulated more than 100-fold.
  • Assays for such activity may employ smooth muscle myosin from a human source, although myosin from other organisms can also be used. Systems that model the regulatory role of calcium in myosin binding may also be used.
  • the in vitro rate of ATP hydrolysis correlates to smooth muscle myosin potentiating activity, which can be determined by monitoring the production of either ADP or phosphate, for example as described in U.S. Pat. No. 6,410,254.
  • ADP production can also be monitored by coupling the ADP production to NADH oxidation (using, for example, the enzymes pyruvate kinase and lactate dehydrogenase) and monitoring the NADH level, by example, either by absorbance or fluorescence (Greengard, P., Nature 178 (Part 4534): 632-634 (1956); Mol Pharmacol 1970 January; 6(1):31-40).
  • Phosphate production can be monitored using purine nucleoside phosphorylase to couple phosphate production to the cleavage of a purine analog, which results in either a change in absorbance ( Proc Nail Acad Sci USA 1992 Jun. 1; 89(11):4884-7) or fluorescence ( Biochem J 1990 Mar. 1; 266(2):611-4). While a single measurement is employed, multiple measurements of the same sample at different times in order may be used to determine the absolute rate of the protein activity; such measurements have higher specificity particularly in the presence of test compounds that have similar absorbance or fluorescence properties with those of the enzymatic readout.
  • Test compounds may be assayed in a highly parallel fashion using multiwell plates by placing the compounds either individually in wells or testing them in mixtures. Assay components including the target protein complex, coupling enzymes and substrates, and ATP may then be added to the wells and the absorbance or fluorescence of each well of the plate can be measured with a plate reader.
  • One method uses a 384 well plate format and a 25 ⁇ L reaction volume.
  • a pyruvate kinase/lactate dehydrogenase coupled enzyme system (Huang T G and hackney D D. (1994) J Biol Chem 269(23):16493-16501) is used to measure the rate of ATP hydrolysis in each well.
  • the assay components are added in buffers and reagents. Since the methods outlined herein allow kinetic measurements, incubation periods may be optimized to give adequate detection signals over the background.
  • the assay is performed in real time to give the kinetics of ATP hydrolysis to increase the signal-to-noise ratio of the assay.
  • Selectivity for smooth muscle myosin may be determined by substituting other myosins in one or more of the above-described assays and comparing the results obtained against those obtained using the cardiac equivalents.
  • Chemical entities identified by the methods described herein as smooth muscle myosin modulators may be further tested in an efficacy screen, such as a screen using strips of permeabilized smooth muscle from, e.g. chicken gizzard.
  • Calcium-sensitive smooth muscle strips are prepared by dissecting chicken gizzard tissue, followed by treatment with 1% Triton X-100 to make the strips permeable to exogenous compounds (Barsotti, R J, et al., Am J. Physiol. 1987 May; 252(5 Pt 1):C543-54). These strips can be stored in 50% glycerol for several weeks at ⁇ 20° C., allowing multiple experiments to be performed with each batch of muscle strips.
  • the chemically skinned gizzard fibers are relaxed when bathed in low calcium solutions (pCa 8), but develop isometric tension when the free calcium of the bathing solution is increased to pCa 5. These fibers can be repeatedly contracted and relaxed by switching between high and low calcium bathing solutions.
  • the chemical entities are administered at a therapeutically effective dosage, e.g. a dosage sufficient to provide treatment of the disease states previously described.
  • a daily dose is from about 0.05 to about 100 mg/kg of body weight, such as from about 0.10 to about 10 mg/kg of body weight or from about 0.15 to about 1 mg/kg of body weight.
  • the dosage range is from about 3.5 to about 7000 mg per day, such as from about 7 to about 700 mg per day or from about 10 to about 100 mg per day.
  • the amount of active chemical entity administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician; for example, a dose range for oral administration may be from about 70 to about 700 mg per day, whereas for intravenous administration the dose range may be from about 700 to about 7000 mg per day.
  • the active agents may be selected for longer or shorter plasma half-lives, respectively.
  • Administration of the chemical entities described herein including pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, sublingually, intramucosally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, and intraocularly (including intraocular injection). Oral, topical, parenteral, and intraocular administration are customary in treating many of the indications recited herein.
  • compositions include solid, semi-solid, liquid and aerosol dosage forms, such as, e.g. tablets, capsules, powders, liquids, suspensions, suppositories, aerosols, and the like.
  • the chemical entities can also be administered in sustained- or controlled-release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, drops and the like, for prolonged and/or timed, pulsed administration at a predetermined rate.
  • the compositions may be provided in unit dosage forms suitable for single administration of a precise dose.
  • the chemical entities may be administered either alone or in combination with a conventional pharmaceutical carrier or the like (e.g. mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like).
  • a conventional pharmaceutical carrier or the like e.g. mannitol, lactose, starch, magnesium stearate, sodium saccharine, talcum, cellulose, sodium crosscarmellose, glucose, gelatin, sucrose, magnesium carbonate, and the like.
  • the pharmaceutical composition may also contain minor amounts of nontoxic auxiliary substances such as wetting agents, emulsifying agents, solubilizing agents, pH buffering agents and the like (e.g. sodium acetate, sodium citrate, cyclodextrine derivatives, sorbitan monolaurate, triethanolamine acetate, triethanolamine oleate.
  • the pharmaceutical composition may contain from about 0.005% to about 95%, for example, from about 0.5% to about 50%, by weight of at least one chemical entity described herein.
  • Actual methods of preparing such dosage forms are known or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences , Mack Publishing Company, Easton, Pa.
  • Pharmaceutical compositions are also referred to as pharmaceutical formulations.
  • the chemical entities may be co-administered with, and the pharmaceutical compositions can include, other medicinal agents, pharmaceutical agents, adjuvants, and the like.
  • the compositions are in the form of a pill or tablet and contain, along with the active ingredient, one or more of a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a lubricant such as magnesium stearate or the like; and a binder such as starch, gum acacia, polyvinylpyrrolidine, gelatin, cellulose, cellulose derivatives and the like.
  • a powder, marume, solution or suspension e.g. in propylene carbonate, vegetable oils or triglycerides
  • Liquid pharmaceutical compositions may, for example, be prepared by dissolving, dispersing, etc. at least one chemical entity and one or more optional pharmaceutical adjuvants in a carrier (e.g. water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like) to form a solution or suspension.
  • a carrier e.g. water, saline, aqueous dextrose, glycerol, glycols, ethanol and the like
  • injectables may be prepared in conventional forms, either as liquid solutions or suspensions, as emulsions, or in solid forms suitable for dissolution or suspension in liquid prior to injection.
  • the percentage of chemical entities contained in such parenteral compositions is highly dependent on the specific nature thereof, as well as the activity of the chemical entities and the needs of the subject.
  • percentages of active ingredient ranging from about 0.01% to about 10% in solution may be used, and may be higher if the composition is a solid which will be subsequently diluted to the above percentages.
  • the composition has from about 0.2% to about 2% of the active agent in solution.
  • compositions comprising at least one chemical entity may be administered intraocularly (including intraocular, periocular, and retrobulbar injection and perfusion).
  • intraocularly the sterile composition is typically aqueous.
  • An appropriate buffer system may be added to prevent pH drift under storage conditions.
  • intraocular surgical procedures such as retrobulbar or periocular injection and intraocular perfusion or injection
  • the use of balanced salt irrigating solutions may be necessary.
  • preservatives may be required to prevent microbial contamination during use.
  • compositions comprising at least one chemical entity may also be administered topically as eye drops, eye wash, creams, ointments, gels, and sprays.
  • the active ingredients When administered as eye drops or eye wash, the active ingredients are typically dissolved or suspended in suitable carrier, typically a sterile aqueous solvent.
  • suitable carrier typically a sterile aqueous solvent.
  • An appropriate buffer system may be added to prevent pH drift under storage conditions.
  • preservatives may be required to prevent microbial contamination during use.
  • compositions comprising at least one chemical entity may also be administered to the respiratory tract as an aerosol or in a solution for a nebulizer, or as a microfine powder for insufflation, alone or in combination with an inert carrier such as lactose.
  • the particles of the composition typically have diameters of less than 50 microns, for example, less than 10 microns.
  • Packaged pharmaceutical compositions comprising a pharmaceutical composition described herein and instructions for using the composition to treat a patient suffering from a disease associated with smooth muscle myosin or non-muscle myosin.
  • the packaged pharmaceutical compositions described herein are also used to treat a patients suffering from a disease associated with smooth muscle myosin selected from hypertension, asthma, chronic obstructive pulmonary disease, bronchoconstrictive disease, glaucoma and other ocular indications, incontinence and other bladder disfunctions, irritable bowel syndrome, pre-term labor, esophogial dysmotility, strokes, subarachnoid hemmorhages, pre-menstrual cramps, erectile dysfunction and other acute and chronic diseases and conditions associated with smooth muscle myosin and/or non-muscle myosin.
  • Also provided is a method of treating or ameliorating a disease associated with smooth muscle myosin or non-muscle myosin in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity described herein.
  • the method of treating or ameliorating a disease associated with smooth muscle myosin or non-muscle myosin described herein is used to treat diseases selected from hypertension, asthma, chronic obstructive pulmonary disease (COPD), bronchoconstrictive disease, glaucoma and other ocular indications, incontinence and other bladder disfunctions, irritable bowel syndrome, pre-term labor, esophogial dysmotility, strokes, subarachnoid hemmorhages, pre-menstrual cramps, erectile dysfunction and other acute and chronic diseases and conditions associated with smooth muscle myosin and/or non-muscle myosin.
  • diseases selected from hypertension, asthma, chronic obstructive pulmonary disease (COPD), bronchoconstrictive disease, glaucoma and other ocular indications, incontinence and other bladder disfunctions, irritable bowel syndrome, pre-term labor, esophogial dysmotility, strokes, subarachnoid
  • Also provided is a method of treating or ameliorating a disease associated with airway wall remodeling in a mammal which method comprises administering to a mammal in need thereof a therapeutically effective amount of at least one chemical entity described herein.
  • smooth muscle myosin is bound to a support and at least one chemical entity is added to the assay.
  • the chemical entity may be bound to the support and the smooth muscle myosin added.
  • Classes of compounds among which novel binding agents may be sought include specific antibodies, non-natural binding agents identified in screens of chemical libraries, peptide analogs, etc. Of particular interest are screening assays for candidate agents that have a low toxicity for human cells.
  • assays may be used for this purpose, including labeled in vitro protein-protein binding assays, electrophoretic mobility shift assays, immunoassays for protein binding, functional assays (phosphorylation assays, etc.), and the like. See, e.g. U.S. Pat. No. 6,495,337.
  • Ethyl 1-chloro-2,7-naphthyridine-3-carboxylate was prepared from 3-cyano-4-picoline according to the published procedures (E. Barbu et. al. Heterocyclic Communications , Vol. 6, No. 1, 2000, 25-28) with some modifications.
  • the precipitate was filtered off and the filtrate was added into a suspension of NaBH 4 in water (1.0 mL) at 0° C.
  • the reaction mixture was stirred at RT for 30 min.
  • LCMS indicated the completion of the reaction.
  • the reaction mixture was acidified to pH 3 by HCl (1N) and extracted with EtOAc (300 mL ⁇ 2). The combined organic layers were washed with saturated NaHCO 3 and brine, dried over Na 2 SO 4 , filtered, and concentrated under reduced pressure.
  • a 500 mL 3-neck RBF was equipped with magnetic stirrer, heating mantle, set-point controller, thermowell, thermocouple and nitrogen bubbler.
  • the flask was charged with 3-(2-chloro-3-fluorobenzyl)-1-((S)-1-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-hydroxypropan-2-yl)-1-methylurea (15.7 g, 41.9 mmol), iodobenzene diacetate (27 g, 2.0 equiv.) and methyl tert-butyl ether (141 mL). The mixture was warmed to ⁇ 55° C.

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